Mitsunobu reagent diethyl azodicarboxylate

Cydization of P-hydroxy-a-amino esters under Mitsunobu reaction conditions is an alternative approach to aziridine-2-carboxylic esters [6b, 13-16], In this case the P-hydroxy group is activated by a phosphorus reagent. Treatment of Boc-a-Me-D-Ser-OMe 13 (Scheme 3.5) with triphenylphosphine and diethyl azodicarboxylate (DEAD), for example, gave a-methyl aziridinecarboxylic acid methyl ester 14 in 85% yield [15]. In addition to PPh3/DEAD [13b, 15], several other reagent combi-... 

A variety of 2,4-oxazolidinedione moieties have been prepared as precursors to A-acyliminium ions. These, in turn, have been used in synthetic approaches to 13-aza-16-oxasteroids, interesting and novel heterocycles, " and natural products such as ( )-p-conhydrine, 294b, ( )-6>-methylpaUidinine, 297, 4-oxa-2-aza-podophyllotoxin, 299, and morphine, 302. Introduction of the 2,4-oxazolidinedione can be achieved by conventional alkylation. However, it is normally introduced through Mitsunobu chemistry using diisopropyl azodicar-boxylate or diethyl azodicarboxylate. " The former reagent is favored by... 

In order to transform the spirocyclic enone 445 to ( )-elwesine (439) and ( )-epielwesine (449), it was treated with boron trifluoride and dimethylsulfide to cleave the Al-carbobenzyloxy protecting group, and cyclization of the resulting amino enone spontaneously ensued to produce ( )-dihydrooxocrinine (447). Reduction of carbonyl function of 447 with sodium borohydride afforded ( )-3-epielwesine (449), which was converted to ( )-elwesine (439) by inversion of the hydroxyl function at C-3 via a Mitsunobu protocol using diethyl azodicarboxylate, triphenylphosphine, and formic acid. Attempted reduction of 447 directly to 439 by a Meerwein-Ponndorf-Verley reduction or with bulky hydride reagents gave only mixtures of 449 and 439 that were difficult to separate. 

Fig. 2.33. Mitsunobu inversion a typical substrate, the reagents, and products (possible preparation of the substrate Figure 2.27). "DEAD" stands for diethyl-azodicarboxylate.

A combination of triphenylphosphine and diethyl azodicarboxylate (the Mitsunobu reagent) is useful for the rapid conversion of aromatic hydroxamic acids (211) to 0-(yV-arylcarbamyl)hydroxamates (212), products of the Lossen rearrangement. In some cases, a spontaneous second Lossen rearrangement occurs to give diarylureas (213), as shown in Scheme 33. The yields of (212) and (213) are 70-85%. The intermediacy of the phosphonium salts (214) has been suggested. 

Nucleophilic Attack at Other Atoms. The mechanism of reactions involving alcohols (or phenols) with the triphenylphosphine-diethyl azodicarboxylate (DAD) reagent (the Mitsunobu reaction) has now been reconsidered in the light of a number of spectroscopic and preparative studies in the past year. In an... 

Diethyl azodicarboxylate (Et02C-N=N-C02Et, DEAD) is a key reagent in the Mitsunobu reaction (sec. 2.7.A.ii) and has also been used for macrolactonization. Reaction of 230 with DEAD gave 15% of 231 in White s synthesis of the antibiotic vermiculine. ... 

The direct cyclodehydration of y0-amino alcohols can be effected with the Mitsunobu reagent (triphenylphosphane/diethyl azodicarboxylate) [16]. 

The Mitsunobu reaction, discovered by Oyo Mitsunobu (1934-2003) in 1967, is one of the most important among modern synthetic reactions. It allows the replacement of the OH group of primary and secondary alcohols with a variety of nucleophiles, with clean inversion of stereochemistry and under mild conditions. The key reagents are triphenylphosphine and a dialkyl azodicarboxylate the latter is very often diethyl azodicarboxylate (DEAD). In addition, a key requirement is that the nucleophile should be acidic (for reasons you ll see below) carboxylic acids, phenols, thiols, imides, and activated carbon acids are all appropriate nucleophiles. 

R] Mitsunobu, 0. Triphenylphosphine-Diethyl Azodicarboxylate. Encyclopedia of Reagents for Organic Synthesis, Paquette, L.A., Ed. John Wiley Sons, Ltd. 1995, 5379. 

Alkyl- and aryl carbodiimides can be prepared under mild conditions from thioureas with diethyl azodicarboxylate/triphenylphosphine (Mitsunobu reagent), typically in yields of around 80% the by-products are triphenylphosphine sulfide and diethyl hydrazodicarboxylate [1278]. The active intermediate in this system is the betaine 1739, which is formed from diethyl azodicarboxylate (DEAD) and triphenylphosphine. Driven by its charge distribution and its chalcogenophilicity, 1739 reacts with the thiourea 1740 to form the P,S bond in 1741. This energy-rich molecule stabilizes by decomposition into three molecules, namely the two byproducts, triphenylphosphine sulfide and diethyl hydrazodicarboxylate, and the desired carbodiimide 1699. Diphenylcarbodiimide 1699 (R = R = Ph) was prepared from N,N -diphenylthiourea 1740 (R = R = Ph) with DEAD and triphenylphosphine in 65% yield [1278]. 

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